1. Field of the Invention
This invention relates to the prevention and treatment of androgen-deprivation induced osteoporosis, bone fractures and/or loss of bone mineral density (BMD) and hot flashes in men suffering from prostate cancer. More particularly, this invention relates to a method of treating, preventing, suppressing, inhibiting, or reducing the risk of developing androgen-deprivation induced osteoporosis, bone fractures and/or loss of BMD and hot flashes in men suffering from prostate cancer, comprising administering to a male subject suffering from prostate cancer cis-clomiphene or a pharmaceutically acceptable salt thereof.
2. Description of Related Art
Prostate cancer is one of the most frequently diagnosed noncutaneous cancers among men in the United States. One of the approaches to the treatment of prostate cancer is by androgen deprivation therapy (ADT). The male sex hormone, testosterone, stimulates the growth of cancerous prostatic cells and, therefore, is the primary fuel for the growth of prostate cancer. The goal of androgen deprivation is to decrease the stimulation by testosterone of the cancerous prostatic cells. Testosterone normally is produced by the testes in response to stimulation from a hormonal signal called luteinizing hormone (LH) which in turn is stimulated by luteinizing-hormone releasing hormone (LHRH). Androgen deprivation therapy is accomplished either surgically by bilateral orchiectomy or chemically by LHRH agonists or antagonists with or without nonsteroidal antiandrogens, like bicalutamide or enzalutamide, or lyase inhibitors like abiraterone.
Current studies suggest that early ADT in patients with micrometastatic disease may indeed prolong survival [Messing E M, et al (1999), N Engl J Med 34, 1781-1788; Newling (2001), Urology 58 (Suppl 2A), 50-55]. Moreover, ADT is being employed in numerous new clinical settings, including neoadjuvant therapy prior to radical prostatectomy, long-term adjuvant therapy for patients at high risk for recurrence following radiation or surgery, neoadjuvant therapy for radiation, and treatment of biochemical recurrence following radiation or surgery [Carroll, et al (2001), Urology 58, 14; Horwitz E M, et al (2001), Int J Radiat Oncol Biol Phy March 15; 49 (4), 947-56]. Thus, more prostate cancer patients have become candidates for and are being treated by ADT. Moreover, these prostate cancer patients are undergoing ADT earlier and longer than in the past, which in some cases may be as long as 10 or more years.
Unfortunately, ADT has significant adverse side effects, like hot flashes, osteoporosis, decreased lean muscle mass, depression and other mood changes, loss of libido, and erectile dysfunction [Stege R (2000), Prostate Suppl 10, 38-42]. Consequently, complications of ADT now contribute significantly to the morbidity, and in some cases the mortality, of men suffering from prostate cancer.
Hot flashes are characterized by the subjective sensation of a rise in temperature in the face and trunk and are accompanied by cutaneous vasodilatation predominantly in the face, throat and extremities, usually followed by profuse sweating. Following the administration of LHRH agonists or antagonists, the steep decline in serum luteinizing hormone and follicle stimulating hormone and rapid and sustained reductions in testosterone and estrogen blood levels results in the release of hypothalamic catecholamines, in particular norepinephrine. These flood the thermoregulation center in the upper hypothalamus, resulting in abnormal and poorly regulated peripheral vasodilatation and the occurrence of hot flushes and perspiration. (Khan et al. 2014, Trends Urol. Men's Health 5 (1), 31-33).
It is estimated that up to 80 percent of patients on ADT will experience hot flashes and up to 27 percent of patients report them as their most troublesome side effect. Most patients will continue to experience these symptoms for as long as they are receiving ADT. Hot flashes can significantly impact on a patient's quality of life. Given that exposure to ADT may be lifelong in the palliative setting and may be two to three years in the adjuvant setting, there is a need to address all associated side effects and deal with them effectively in order to improve compliance with treatment and quality of life. (Reviewed in Khan 2014).
It is well established that the bone mineral density (BMD) of males decreases with age. Decreased amounts of bone mineral content and density correlates with decreased bone strength and predispose to fracture. The molecular mechanisms underlying the pleiotropic effects of sex-hormones in non-reproductive tissues are only beginning to be understood, but it is clear that physiologic concentrations of androgens and estrogens play an important role in maintaining bone homeostasis throughout the life-cycle. Consequently, when androgen or estrogen deprivation occurs, there is a resultant increase in the rate of bone remodeling that tilts the balance of resorption and formation in the favor of resorption, contributing to an overall loss of bone mass. In males, the natural decline in sex-hormones at maturity (direct decline in androgens as well as lower levels of estrogens derived from peripheral aromatization of androgens) is associated with the frailty of bones. Moreover, an important side effect in men suffering from prostate cancer undergoing ADT is the development of bone loss leading to osteoporosis and bone fractures. Loss of BMD occurs in the majority of patients being treated by ADT by 6 months.
New innovative approaches are urgently needed at both the basic science and clinical levels to decrease the incidence of androgen-deprivation induced hot flashes and bone loss and fractures in men suffering from prostate cancer on ADT.